Blood glucose was 1.9 mmol/l at the time. An FFA level of 3,800 micromol/l is impressively high. She was generating a small amount of ketones.

No one would argue with intravenous glucose at this point, the question is about how she got here.

So. The problem here does not (as I'd initially thought) appear to insulin induced suppression of FFAs to a level at which beta oxidation fails to support metabolism. FFAs are very high, even for an P479L person after a short fast. With ketones starting to be produced (and low blood glucose) I feel it is reasonable to assume that her liver glycogen is depleted and, while some fatty acids are entering the hepatocytes, not enough of them are being oxidised to support ketogenesis. Glycogen is being depleted to keep liver cells functional. Gluconeogenesis from protein is unable to meet the hepatic (and whole body) demand for glucose calories in the situation of limited access to FFA calories.

However much glycogen derived glucose you consider that the ancestral diet contained I feel it is very, very unlikely to be greater than the glucose and fructose of a modern diet. I feel that getting enough glycogen in to the liver to fully fuel its metabolism in the absence of adequate fatty acid oxidation is a non starter. The P479L mutation was not "permitted" by high oral carb loading, it was permitted by conditions which facilitated fatty acid oxidation. You don't have to agree.

What starts to look much more interesting is what controls CPT-1a activity and how this might vary from the ancestral diet to the modern diet.

The paper makes the point that omega 3 fatty acids appear to up regulate fatty acid oxidation (in rats at least) by the liver. If this is true in humans then a high level of omega 3 fatty acids from marine fats might up regulate fatty acid oxidation to a level which no longer necessitates the depletion of hepatic glycogen derived form oral glucose intake or protein catabolism.

In support of this is that the distribution of P479L within Alaska is not uniform, it's significantly commoner in the coastal regions compared to the inland areas.

"The allele frequency and rate of homozygosity for the CPT-1a P479L variant were high in Inuit and Inuvialuit who reside in northern coastal regions. The variant is present at a low frequency in First Nations populations, who reside in areas less coastal than the Inuit or Inuvialuit in the two western territories"

I'm open to other explanations, there are papers suggesting that the mutation helps to preferentially dispose of omega 6 PUFA, with omega 3 fatty acids as the facilitator.

In summary: Maintaining adequate FFA oxidation to avoid glycogen depletion looks to be the core need in P479L. A high fat diet with a large proportion of omega 3 fats might be a plausible way of maintaining adequate hepatic fatty acid oxidation. Hyperglycaemia (via Crabtree effect) looks to be anathema. Glycogen loading with a normal starch/sugar based modern diet is clearly ineffective to prevent hypoglycaemia for some individuals. Resistant starch as a reliable nightly adjunct to infant feeding seems very unlikely in the ancestral diet. Repeated periods of fasting were probably routine when hunting was poor and does not appear to have selected against P479L in weaned children. Unweaned children are unlikely to be exposed to fasting, provided milk was available from lactation.

Well, there are some more thoughts on the biochemistry.

People clearly have very differing ideas of what the Inuit did or did not eat as an ancestral diet. The P479L gene eliminates the need for source of dietary glucose to explain very limited levels of ketosis recorded in the Inuit. While it is perfectly possible to invoke a high protein diet to explain a lack of ketosis in the fed state this goes nowhere towards explaining the limited ketosis of fasting. P479L fits perfectly well as an explanation.

I have some level of discomfort with using the Inuit as poster people for a ketogenic diet. That's fine. They may well have eaten what would be a ketogenic diet for many of us, but they certainly did not develop high levels of ketones when they carried the P479L gene.

However. Over the months Wooo and I seem to have come to some sort of conclusion that, while systemic ketones are a useful adjunct, a ketogenic diet is essentially a fatty acid based diet with minimal glucose excursions and maximal beta oxidation. Exactly how important the ketones themselves are is not quite so clear cut. From the Hyperlipid and Protons perspective I would be looking to maximise input to the electron transport chain as FADH2 at electron-transferring-flavoprotein dehydrogenase and minimise NADH input at complex I. Ketones do not do this. Ketones input at complex II, much as beta oxidation inputs at ETFdh, but ketones also generate large amounts of NADH in the process of turning the TCA from acetyl-CoA to get to complex II, which ETFdh does not. I'm not a great lover of increasing the ratio of NADH to NAD+. These are my biases.

Confirming that the Inuit are not poster boys for ketosis is a "so what?" moment for me. Using their P479L mutation to argue against ketogenic diets is more of a problem. It's a massive dis-service to any one of the many, many people out there who are eating their way in to metabolic syndrome to suggest that a ketogenic diet is a Bad Thing because no one has lived in ketosis before. Even the Inuit didn't! My own feeling is that everyone comes from stock who occasionally practiced and survived intermittent fasting so we are should be adapted to this. I'd guess that if you are of Siberian, Inuit or First Nations extraction you might benefit from Jay Wortman's oolichan oil as part of a ketogenic diet.

I'm always amazed by the concept that a ketogenic diet might be temporarily therapeutic but must be discontinued because it eventually becomes Bad For You. It reminds me so much of the converse concept that low fat diets, which might worsen every marker of health which people may care to look at, will deliver major benefits at some mythical future date.

Ultimately, point scoring on the internet about what the Inuit did or didn't eat shouldn't destroy people's chances of health. Destroying a circular argument about Inuit diets may may the destructor feel good. Destroying the feet, eyes and kidneys of a person with type 2 diabetes, who need a ketogenic diet, as a spin off from that victory must be difficult to live with. I don't know how anyone can do this.

The paper itself is largely an account of the detective work involved in pinning down a specific mutation which has been positively selected for in a Siberian population living in the Arctic. The same mutation is also present in non related groups inhabiting the Arctic areas of northern America. The mutated gene is very common and frequently homozygous. It puts a leucine in the place of a proline in CPT-1a, the core enzyme for getting long chain fatty acids in to mitochondria. Putting a leucine where there should be a proline means the protein is basically f*cked. The mutation is linked, not surprisingly, to failure to generate ketones in infancy and can be associated with profound hypoglycaemia, potentially causing sudden death.

From the evolutionary point of view we have here a mutation which is significantly lethal at well below reproductive age, so it should have been weeded out because affected individuals are less likely to live long enough to pass on the gene. But it has been highly positively selected for in several populations, the common factors being cold climate and minimal access to dietary carbohydrate. It's a paradox.

Following a link in the paper gives us this abstract, with this snippet:

A value 6% with an SD of 5% suggests to me that some of these people may well have a CPT-1a function very close to zero. How common is the mutation?

"We screened 422 consecutive newborns from the region of one of the Inuit families for this variant; 294 were homozygous, 103 heterozygous, and only 25 homozygous normal; thus the frequency of this variant allele is 0.81"

I think "very common" is a reasonable description.

How dangerous is it?

"Three of the seven patients and two cousins had hypoketotic hypoglycemia attributable to CPT-Ia deficiency"

Quite dangerous.

The next thing we can do is google CPT-1a deficiency and have a look what needs to be done to stay alive if you carry this gene.

Clearly, if you can't transport LCFAs in to your mitochondria, you should run your metabolism on glucose/pyruvate and avoid the dysfunctional fatty acid transporter. This means raw corn starch, as we have seen used (probably wrongly) for glycogen storage diseases. Properly cooked starches are too short acting to reliably keep a child alive all through the night. They aren't safe enough.

Of course MCT oils have a role too. A CPT-1a defect has no effect on MCT metabolism so these can be used either directly by tissues or indirectly via liver/glial produced ketones.

LCFAs, unable to be metabolised, accumulate in the tissues as a storage disease. The advice is to avoid them as far as possible.

So the archetypical CPT-1a defect tolerant environment would seem to be a person sitting on a South Seas Island beach by a pile of coconuts chewing on a raw yam, with copious flatus night and day.

But it's not.

The CPT-1a defect evolved in multiple non related populations where both starch and MCT were very notable by their near-complete absence. It's an Arctic selected gene. No starches. No coconuts.

Let's take a speculative look at what is going on.

Living on a very low carbohydrate diet is associated with chronically elevated free fatty acids, chronically low levels of insulin and an ignorance of glucose. i.e. the body ignores glucose. Synthesise what glucose is needed but, beyond that, who cares?

Living in a sea of free fatty acids, which are taken up in to cells in a largely concentration dependent manner, allows an increased gradient to push FFA-CoA at any residual function in CPT-1a. It would appear, from the evolutionary perspective of Arctic inhabitants, that near ketogenic levels of FFAs are adequate even if you have the proline to leucine substitution at amino acid 479 in CPT-1a. You can do enough beta oxidation to cope.

Of course, the minute you lower free fatty acids, perhaps to the level of a post prandial starchivore, beta oxidation is going to grind to a halt without the concentration gradient effect. This is pathological. The temporary fix of substrate level ATP synthesis and related pyruvate supply to the mitochondria is fine for a while, but any reactive hypoglycaemia is going to be potentially fatal, especially if you are asleep or food deprived at the time. We know that insulin suppresses lipolysis at levels which don't budge GLUT4s. When insulin has suppressed lipolysis and blood glucose is low, FFAs might be fatally limited.

If you have the mutation but you never do the starchivore thing your FFAs are high 24/7, whether you have just chewed on a lump of seal blubber or not. No paper in the reference list appears to have looked at the FFA levels of children with this mutation on a mixed diet, let alone on the ancestral fat based diet of the polar regions. Given sustained very high levels of FFAs, you might even make some ketones.

If free fatty acids are high and there is no insulin to divert them in to storage, all of the nasty storage diseases associated with CPT-1a dysfunction might well disappear. This is the situation where the mutation allows carriers to thrive.

I think elevated free fatty acids, without elevated insulin, is a recipe for the tolerance of this mutation.

But the mutation is not just tolerated. This is no neutral mutation, it is positively advantageous. The prevalence of the mutated gene is far from random. Why is it beneficial?

This is not quite so simple.

Uncoupling is one component. Uncoupling respiration generates heat. There might just be a positive advantage to running your metabolism fairly uncoupled in a very low temperature environment. Elevated FFAs are completely essential to uncoupling and heat generation. Limiting fatty acid removal from the cytoplasm to the mitochondria might be a facilitator of uncoupling. It's FFAs on the cytosolic side of UCPs which facilitate proton translocation. Having a higher level of cytoplasmic FFAs at a given level of plasma FFAs might give an advantage over the normal level of uncoupling seen under near ketogenic diet conditions.

The second possibility is that, once you have established high enough levels of FFAs to push through the CPT-1a bottle neck, you simply run at this level flat out, all the time. One of the features of the CPT-1a from the modified gene is that it fails to be inhibited by malonyl-CoA. Even with limited CPT-1a activity there must be times at which ATP synthesis exceeds metabolic requirements and fatty acid transport ought to slow. There is no longer any brake to be applied to FFA transport if excess acetyl-CoA, exported to form malonyl-CoA in the cytoplasm, fails to inhibit CPT-1a . Oversupply of ATP within the matrix is likely to provide optimal uncoupling conditions, in excess of those from a ketogenic diet with regulated fatty acid uptake. That would be my guess. If it's cold enough, this might make the difference between survival or not. It keeps you warm, especially when you are asleep and the TCA should be quiescent.

Flicking through other references in the paper it does appear that indigenous Siberian people do have an elevated resting metabolic rate. In fat free mass it is 17% above calculated values i.e. they are uncoupled.

Finally, adults are not affected by the hypoglycaemia syndrome. My presumption is that, after puberty, they are sufficiently insulin resistant to have adequate FFAs present to maintain relatively normal mitochondrial function. It's the children who need their ancestral diet.

People with glycogen storage diseases die of hypoglycaemia (amongst other problems). We know that a deeply ketogenic diet both protects from hypoglycaemia and sets the body up to run perfectly well without any dietary glucose, which might be lost to glycogen stored permanently in the liver/muscles. There is every justification for giving the finger to cornstarch here and the folks suggesting a modification of ketogenic eating appear to be on fairly safe biochemical ground.

For the P497L mutation everything from the evolutionary perspective suggest that a very high FFA inducing diet may be equally efficacious. But the risks associated with failure, from the occasional safe starch meal or unsafe birthday cake at a party, carries the potential for catastrophe once insulin puts free fatty acids in to free fall.

Peter

BTW: You just have to wonder if any other CPT-1 mutations might behave in a similar manner to the P497L change in the Arctic... Could it be bye-bye time for cornstarch?

About Me

I am Petro Dobromylskyj, always known as Peter. I'm a vet, trained at the RVC, London University. I was fortunate enough to intercalate a BSc degree in physiology in to my veterinary degree. I was even more fortunate to study under Patrick Wall at UCH, who set me on course to become a veterinary anaesthetist, mostly working on acute pain control. That led to the Certificate then Diploma in Veterinary Anaesthesia and enough publications to allow me to enter the European College of Veterinary Anaesthesia and Analgesia as a de facto founding member. Anaesthesia teaches you a lot. Basic science is combined with the occasional need to act rapidly. Wrong decisions can reward you with catastrophe in seconds. Thinking is mandatory.
I stumbled on to nutrition completely by accident. Once you have been taught to think, it's hard to stop. I think about lots of things. These are some of them.

Organisation (or lack of it)!

The "labels" function on this blog has been used to function as an index and I've tended to group similar subjects together by using labels starting with identical text. If they're numbered within a similar label, start with (1). The archive is predominantly to show the posts I've put up in the last month, if people want to keep track of recent goings on. I might change it to the previous week if I ever get to time to put up enough posts in a week to justify it. That seems to be the best I can do within the limits of this blogging software!